Impaired dendritic cell maturation and cytokine production in patients with chronic mucocutanous candidiasis with or without APECED. Clin Exp Immunol

Institute for Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Clinical & Experimental Immunology (Impact Factor: 3.04). 01/2009; 154(3):406-14. DOI: 10.1111/j.1365-2249.2008.03778.x
Source: PubMed


Patients with chronic mucocutaneous candidiasis (CMC) suffer persistent infections with the yeast Candida. CMC includes patients with autoimmune regulator (AIRE) gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, and dendritic cells (DCs), as central orchestrators, may underlie pathogenic disease mechanisms. In 29 patients with CMC (13 with APECED) and controls, we generated monocyte-derived DCs, stimulated them with Candida albicans, Toll-like receptor-2/6 ligand and lipopolysaccharide to assess cytokine production [interleukin (IL)-12p70, IL-23, interferon (IFN)-gamma, IL-2, tumour necrosis factor (TNF)-alpha, IL-6, transforming growth factor-beta, IL-10, IL-5, IL-13] and cell-surface maturation marker expression (CD83, CD86, human leucocyte antigen D-related). In both APECED and non-APECED CMC patients, we demonstrate impairment of DC function as evidenced by altered cytokine expression profiles and DC maturation/activation: (1) both groups over-produce IL-2, IFN-gamma, TNF-alpha and IL-13 and demonstrate impaired DC maturation. (2) Only non-APECED patients showed markedly decreased Candida-stimulated production of IL-23 and markedly increased production of IL-6, suggesting impairment of the IL-6/IL-23/T helper type 17 axis. (3) In contrast, only APECED patients showed DC hyperactivation, which may underlie altered T cell responsiveness, autoimmunity and impaired response to Candida. We demonstrate different pathogenic mechanisms on the same immune response pathway underlying increased susceptibility to Candida infection in these patients.

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Available from: Andrew J Cant, Jul 25, 2014
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    • "Following phagocytosis, DCs migrate to the lymph nodes where the Candida antigen is processed and presented on the surface of the DC to naïve CD4+ T-cells (84–88). Interaction between DCs and T-cells cause the latter to differentiate into mature effective T-cells (89). The type of T-cell generated is thought to be under direction of the DC and examples of effective T-cells include T-helper 1 (Th1), T-helper 2 (Th2), T-helper 17 (Th17), and regulatory T-cells (Tregs). "
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    • "The lack of overt staphylococcal disease in most APS-I patients may result from residual IL-17 immunity, as observed to an even greater extent in patients with IL-12p40 and IL-12R1 deficiencies who also control staphylococcal infections normally (Filipe-Santos et al., 2006). In any case, proof that human IL-17 cytokines play an essential role in immunity to Candida will require the identification of mutations specifically impairing IL-17 immunity in other patients with inherited, isolated CMC without APS-I (Ryan et al., 2008; Hong et al., 2009 "
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